Persons with hemochromatosis were recruited via Internet-based educational and referral information and by letters to area physicians. Comprehensive care and phlebotomy therapy were offered free of charge regardless of whether subjects met criteria for allogeneic donation. Hemoglobin of 12.5 g/dL, the regulatory threshold for blood donation in the U.S., was used as the threshold for performing phlebotomy, and decreases in the mean corpuscular volume (MCV) and ferritin were used to guide the endpoints of therapy. 503 subjects with iron overload were enrolled as of September 9, 2014. 67% of subjects were homozygous for the C282Y mutation in the HFE gene, 69% met eligibility criteria for allogeneic donation, and 57% were previous blood donors. A median of 25 weekly or biweekly phlebotomies (range 7-99) were performed before the ferritin reached the targeted endpoint of l 50-10050 mcg/L. The median phlebotomy interval necessary to keep the MCV at this level during maintenance therapy was 20 weeks. Hemochromatosis donations were safe: no incident seroconversions for agents of transfusion-transmissible disease occurred during 11802 donations. As of September 2013, hemochromatosis donors were contributing 600 units of red cells yearly, including 8% of the units collected for allogeneic use in the NIH Clinical Center, and 150 units per year distributed for research use to NIH investigators from donors who did not meet standard eligibility criteria. Family member screening and counseling were facilitated by concentrating the care within the Blood Center. During the 13 years that this study has been active, and the results disseminated at meetings and in the medical literature, the number of Blood Centers nationwide that have instituted hemochromatosis donor programs has grown from 26 to 163. Our data demonstrate that hemochromatosis subjects can safely and significantly augment the allogeneic blood supply. Provision of phlebotomy therapy in the Blood Center, unrestricted by considerations of insurance reimbursement or suitability for donation, can improve access to care and remove incentives for incomplete risk disclosure. Evaluations performed to date in this cohort indicate that there is a higher than expected incidence of thyroid abnormalities in hemochromatosis subjects, most commonly subclinical hypothyroidism. Thyroid function abnormalities were found in 30% of female subjects with homozygosity for the C282Y HFE mutation. A recent series of cardiology studies in these patients indicate that C282Y homozygotes have a statistically increased incidence of mild, subclinical abnormalities in atrial contractility and exercise-associated arrhythmias when compared to normal subjects, and these changes may be associated with elevated serum markers of oxidative stress. Left ventricular contractility and response to stress were found to be normal in C282Y homozygotes compared with control subjects. A comprehensive analysis of arthritis in these subjects revealed that 11.3% (38 of 337) C282Y-homozygous versus 1.2% (2 of 166) non-homozygous subjects underwent a total of 34 total hip, 16 total knee, and 9 total ankle replacements. The frequency of total joint replacement was significantly greater in C282Y-homozygotes than in the control group. The cumulative risk of total joint replacement hemochromatosis subjects was 31% by age 75. Among C282Y homozygotes, the risk of total joint replacement was markedly greater in subjects with initial ferritin levels greater than the median value of 735 mcg/L. Among the estimated 23,966 Caucasian U.S. males age 40-79 undergoing total hip replacement each year, the data suggest that 3-4% are C282Y-homozygous. Current efforts are focused on overcoming community and Blood Center resistance to use of hemochromatosis subjects as allogeneic blood donors, on dissemination of best phlebotomy practices as exhibited in this study, on critical examination of the role of double red cell donation by apheresis in the management of HH subjects, and on assessing changes in serum non-transferrin bound iron levels during therapy